1. Technical Held
Embodiments of the subject matter disclosed herein relate generally to apparatuses, methods and systems and, more particularly, to devices, processes, mechanisms and techniques for measuring size distribution and/or concentration of particles.
2. Description of Related Art
The ability to measure and to quantify the type, behavior, and/or characteristics of particles (e.g., measurement of individual size and local number and/or mass concentrations) is of utmost importance in a large number of applications of interest, including, for example, medical diagnostics, food preparation, environmental sciences in general, and the control of industrial and vehicular emissions, to name just a few. More specifically, in the medical diagnostics area, for example, it is well established that a risk for a particular disease (e.g., Coronary Heart Disease, or CHD) can be reasonably assessed by measuring mobility spectra (i.e., the mass distribution as a function of particle size) of lipoprotein particles in the blood of a patient. There are also many other medical diagnostics that are based on the ability to measure protein sizes and concentrations, including the ability to identify a genetic disease based on the variation of size and concentration of hemoglobin. In addition, in the area of aerosol and nanotechnology sciences, as applied to environmental concerns, for example, there exist several requirements to measure the size and/or type of a particle that can be related to emissions controls, environmental measurements of how much soot or particulate matter a person may be exposed to in ambient airflows, how much dust may be exhausting into the atmosphere from industrial source emissions, or the quantification of size and concentration of particulate matter in the atmosphere and their effect on the earth's climate. The need to perform particle-related measurement is further evidenced by the large number, and ever more stringent, governmental regulations dealing with the subject.
A variety of measurement techniques have been used to determine the size of particles smaller than 1 μm in diameter. Optical particle detectors determine particle size from the amount of light scattered into a photodetector when a particle passes through a single laser beam. This method is limited to particles larger than about 0.05 μm in diameter. Aerodynamic particle-acceleration lens systems have been designed to accelerate particles according to their size—smaller particles attaining higher velocity than larger particles when a gas containing such particles is accelerated through a nozzle. When the accelerated particles are directed to pass through two precisely spaced laser beams, light scattered by the transiting particle produces two pulses on a photodetector, thus revealing the time it takes a particles to pass through the two laser beams, from which particle velocity can be deduced. This technique is also limited to particles larger than about 0.05 μm in diameter. Aerosol impactors can be used to deposit selected sizes of particles onto a collection surface or into a collection fluid. Chemical analysis and the weight of the collected particles can then be used to construct particle size distributions.
In applications involving macromolecules (e.g., DMA, RNA, and proteins, including their fragments as well as small particles less than 100 nm in diameter), several conventional sizing techniques and/or devices are known, namely, gel electrophoresis, Differential Mobility Analyzers (or DMA), drift tubes, and mass spectrometers, although the latter is used to determine the size of molecules, it actually provides only molecular mass.
Gel electrophoresis is used in clinical chemistry to separate proteins by charge and or size and in biochemistry and molecular biology to separate a mixed population of DNA and RNA fragments by length, to estimate the size of DNA and RNA fragments, or to separate proteins by charge. Nucleic acid molecules are separated by applying an electric field to move the negatively charged molecules through a gel matrix. Shorter molecules move faster and migrate farther than longer ones because shorter molecules migrate more easily through the pores of the gel. Gel electrophoresis can also be used for separation of nanoparticles. Those of ordinary skill will however recognize that gel electrophoresis is a technique that requires a substantial amount of time for completion of any given measurement. Additionally, the position of a band in a gel electrophoresis lane needs to be compared to size standards, typically molecules of known molecular weight, in order to estimate the molecular weight of the material in the band. The need to calibrate gel lanes adds to the effort involved and makes the method a relative measurement technique.
Differential electrical mobility analyzers may be used to determine the size distribution of particles smaller than a micrometer in diameter, in this method, a cloud of charged aerosol particles is drawn between two electrodes, such as the annular space between two concentric cylinders. Voltage applied to the cylinders deflects particles of a predictable size into a particle detector. By scanning the voltage applied to the cylinders, the size distribution of the particles is obtained. U.S. Pat. No. 6,230,572 (which is incorporated herein by reference in its entirety) discloses an example of such an apparatus.
It has been shown (see, for example, U.S. Pat. Nos. 7,259,018, 7,851,224, and 7,713,744, the entire contents of which are incorporated herein by reference) that electrical mobility spectra of lipoprotein particles isolated from human serum reveal simultaneously the size distributions of HDL, LDL, IDL and VLDL particles in a plasma sample, thus revealing a useful technique for assessing risk of CHD. The capability of mobility measurements to span the HDL and LDL lipoprotein size range in one spectrum may be one of the advantages of the use of mobility technology. Conventional gel electrophoresis systems require two different types of gels to reveal the size distributions of HDL particles separately (Agar gel) from LDL, IDL and VLDL particles (gradient density polyacrylamide gel). An example of a conventional measurement of the mobility spectra of lipoproteins obtained from five patients participating in a cholesterol study is illustrated in FIG. 1. The patients were selected on the basis of gel-derived lipoprotein patterns that characterized three of the patients at risk for CHD (type B pattern at high risk for CHD), two of the patients with lower risk for CHD (type A pattern at lower risk for CHD) and one patient having an intermediate risk. Ion mobility spectra provided data to predict the same level of risk for each patient. Mobility-derived lipoprotein profiles, such as these, are acquired substantially faster than those obtained by gel electrophoresis used to separate lipoprotein subclasses. However, those of ordinary skill in the art will appreciate that conventional DMA technology faces several challenges, including limited resolution to resolve profiles of lipoprotein particles that confer diagnostic value when measured using other techniques, such as gradient gel electrophoresis, and high capital and operating costs.
Another conventional device used to make measurements of ions is a drift tube. FIG. 2 illustrates a conventional cylindrical drift tube 10. In operation, voltage is applied to each of the ring-shaped electrodes 12 in such a way that the resulting electrical field inside the drift tube is constant along the longitudinal axis of the tube. An ion gate 14 is placed at the entrance to the drift tube and provides a way to introduce a pulse of ions 15 from an ion source 18 into the electric field generated inside the drift tube. In the example illustrated in FIG. 2, the ion population is bimodal, i.e., it comprises a group of heavy ions 20 and another of light ions (22). An ion detector 18 is located at the opposite end of the drift tube and responds to ions when they strike the detector, in the exemplary illustration of FIG. 2, the detector is a flat metal plate to which a current amplifier is connected and when a pulse of charged particles hits the detector, a momentary rise in detector current is observed, as illustrated in the Time-of-Flight (or TOF) spectrum 24 inserted in FIG. 2 for the bimodal ion group considered for this example, ion drift tubes are commonly purged with a flow of gas to minimize the influence of solvent vapor on drift time. Ion velocities resulting from the electrical field inside the drift tube are substantially higher than gas velocities in the purge gas and, as a consequence, gas velocity has little influence on ion trajectories and does not significantly impact ion arrival time distributions. However, the performance of conventional drift tubes for particles having drift velocities close to the velocity of the purge gas is substantially degraded, as understood by those of ordinary skill in the applicable arts.
Therefore, based at least on the above-noted challenges with conventional devices to measure the concentration and size of particles, it would be advantageous to have improved devices to accomplish the summarized tasks, among others, with increased measurement accuracy (particularly in embodiments operating on first principles without the need for calibration), lower cost of manufacturing and operation, reduction on the time required for measurements, and minimization or elimination of the effect of purge gas velocity on the velocity of the particles being measured, while, in some embodiments of the subject matter disclosed herein, increasing the resolution of such measurements by mathematically deconvolving from the measurements the effect of a spread in arrival times due to diffusion and non-ideal background flow velocity variations.